SUMMARY Primary hypertension (HTN) is a major risk factor for cardiovascular disease, with salt sensitive HTN (SSHTN) accounting for 51% of cases. As increased sympathetic nerve activity (SNA) is known to play a key role in the development of SSHTN; we propose a study to investigate the mechanisms whereby hyperactivity of brain prorenin receptor (PRR), a hormone receptor, may critically influence SNAdysregulation,contributingtoSSHTNdevelopment. The hypothalamic paraventricular nucleus (PVN) plays a crucial role in both salt-sensing mechanisms and sympathetic outflow control. Lesions in the PVN prevent high- salt induced HTN in the Dahl salt sensitive (Dahl S) rat, an animal model for human genetic SSHTN. PVN sympathetic efferent activity is modulated by multiple factors including nitric oxide (NO), and excessive NO, produced by up-regulated inducible nitric oxide synthase (iNOS), can lead to HTN. The PVN is notable for its high expression of PRR. Specific knockout of PRR in neurons blocks the development of SSHTN in DOCA-salt mice, and animal model for human secondary SSHTN. In addition, evidence from literature and our preliminary data shows that (1) When high salt intake induces HTN in Dahl S rats, it also increases [Na+] in the brain cerebrospinal fluid (a consequence of abnormal sodium transport across the blood brain barrier) and induces increased mRNA levels of P R R , iNOS and Fra1, a component of transcription factor AP1, in the PVN; (2) In normotensive Sprague Dawley (SD) rats, intracerebroventricular (ICV) administration of hypertonic saline increases SNA, blood pressure (BP) as well as mRNA levels of iNOS and Fra1 in the PVN of SD rats; (4) acute PVN PRR activation increases sympathetic outflow, and chronic overexpression of PRR results in BP elevation in SD rats; and (5) PRR activation in cultured hypothalamic neurons from SD rats leads to a robust increase in mRNA levels of Fra1 and iNOS. This increase in iNOS can be blocked by AP1 inhibitor. All evidence considered, we hypothesize that high salt intake elicits PRR activation in the PVN which, through a process dependent upon AP1-iNOS driven production of excessive NO, enhances sympathetic outflow, ultimately resulting in development of SSHTN. W e propose the following specific aims to test our hypothesis: (1) Genetic knockdown of PVN PRR will lead to a long-term decrease in sympathetic outflow and prevent SSHTN development; (2) Elucidation of the mechanisms of AP1-iNOS mediated PVN PRR-associated signal transduction will provide insight into development of SSHTN. Most importantly, we will strengthen the research environment at Michigan Technological University and expose our students to the potentials and benefits of biomedical research.